The present invention relates generally to prior mechanical ventilation and liquid ventilation techniques.
Mechanical ventilators are clinical devices that cause airflow into the lungs. For ventilatory support in the setting of intensive care, volume-controlled or pressure-regulated positive pressure ventilators are generally used. Such devices force air into the lungs during inspiration but allow a return to ambient pressure during spontaneous exhalation. In volume-controlled ventilation, a preset tidal volume is delivered to the patient regardless of the pressure required to deliver the inspiratory volume. In pressure-regulated ventilation, peak inspiratory pressure is limited, as determined by the operating console. Controls are typically also provided to select the inspired O.sub.2 mixture, inspiration and expiration time, and ventilatory frequency. Such conventional ventilators are available from several manufacturers.
Liquid ventilation is a radically different technique that involves temporarily filling pulmonary air passages with an oxygenated liquid medium. It was first demonstrated that mammals submerged in hyperoxygenated saline could breathe liquid and successfully resume gas breathing in 1962 (1; see appended Citations). However, this approach to liquid ventilation (LV) was eventually abandoned, due to the practical difficulties of dissolving sufficient quantities of O.sub.2 in saline (even at hyperbaric pressures), and because saline rinses away much of the surfactant lining the lung alveoli (2). These problems were overcome in 1966 by Dr. Leland Clark, who was the first to use perfluorocarbon liquids (now oxygenated at atmospheric pressure) to support the respiration of mice, cats, and puppies (3).
Perfluorocarbon (PFC) liquids are derived from common organic compounds by the replacement of all carbon-bound hydrogen atoms with fluorine atoms. These liquids are clear, colorless, odorless, nonflammable, and essentially insoluble in water. PFC liquids are denser than water and soft tissue, and have low surface tension and, for the most part, low viscosity. Perfluorocarbon liquids are unique in their high affinity for gases, dissolving more than 20 times as much O.sub.2 and over 3 times as much CO.sub.2 as water. Like other highly inert carbonfluorine materials, perfluorocarbon liquids are extremely nontoxic and biocompatible. For a review, see (4).
To date it has been clearly established that mammals can breathe (total ventilation support) oxygenated perfluorocarbon liquids for long periods (&gt;3 hours) and return to gas breathing without untoward long-term effects (5,6). Additional studies have shown that no adverse morphological, biochemical, or histological effects are seen after perfluorocarbon ventilation (7,8). Perfluorocarbon liquids have also been investigated for lung lavage (washing) (9), and have been found to be effective in rinsing out congestive materials associated with Respiratory Distress Syndrome (RDS) in adult humans (10). While total respiratory support of both lungs via perfluorocarbon liquids is not without side effects, these effects are minor and transient (mild acidosis, lower blood pO.sub.2, increased pulmonary vascular resistance, and decreased lung compliance) (11-14). Other biomedical applications of perfluorocarbon liquid ventilation have received serious research effort (15,16). Lung cancer hyperthermia via ultrasound and/or convection with perfluorocarbon liquids has been reported (17).
In particular, perfluorocarbon liquid ventilation is a promising treatment of respiratory distress syndromes involving surfactant deficiency or dysfunction. Elevated alveolar surface tension plays a central role in the pathophysiology of the Respiratory Distress Syndrome (RDS) of prematurity (18,19) and is thought to contribute to lung dysfunction in the Adult Respiratory Distress Syndrome (20). Perfluorocarbon liquid ventilation is effective in surfactant-deficient premature animals because it eliminates air/fluid interfaces in the lung and thereby greatly reduces pulmonary surface tension (11). Liquid ventilation can be accomplished at acceptable alveolar pressures (21) without impairing cardiac output (22) and provides excellent gas exchange even in very premature animals (23). A successful human trial of perfluorocarbon liquid ventilation in very premature infants with RDS has recently been reported (24). Recall that, in liquid ventilation, perfluorocarbon liquid is extracorporeally oxygenated and purged of carbon dioxide, and tidal breaths of the liquid are mechanically cycled into and out of the lungs using an investigational device. Unfortunately, such extracorporeal liquid ventilators are not commercially available. Moreover, enthusiasm has also been dampened by the apparent lack of a safe fall-back support system to protect the patient should it be necessary to suddenly discontinue the liquid breathing treatment. Furthermore, because the perfluorocarbon is oxygenated and purged of carbon dioxide outside the body, and cyclically delivered to the lungs, a large and expensive priming volume of perfluorocarbon is required to fill the liquid breathing device. Such operational disadvantages and safety concerns have greatly hindered more widespread use of the otherwise promising liquid ventilation techniques.